Antidepressant medications variably affect weight and metabolic outcomes and pose risks related to obesity. The clinical relevance of these effects across randomized trials remains unclear. Understanding these effects can inform treatment selection for patients with obesity. Relevant studies were identified through searches of PubMed, MEDLINE, Cochrane Library, Web of Science, PsycINFO, Scopus, and Embase. Studies were included if they were randomized controlled trials reporting whether a Food and Drug Administration-approved antidepressant agent was associated with obesity-related measures as either a primary outcome, secondary outcome, or safety outcome. Of the 222 identified records, 19 eligible studies (all randomized controlled trials, comprising 24,256 participants) met the inclusion criteria. In trials that combined pharmacotherapy with behavioral/psychotherapeutic interventions, fluoxetine was associated with larger weight reductions (−7.89 kg with fluoxetine + metformin vs. −0.48 kg in a comparator group in one trial), and cognitive behavioral therapy + fluoxetine produced greater reductions in binge-eating disorder samples than fluoxetine alone (≈5.1 kg vs. ≈2.1 kg). Bupropion monotherapy produced modest but sustained weight loss in some studies (reductions up to 2.4 kg over 52 weeks), while the naltrexone–bupropion combination produced the largest and most reproducible benefits when delivered with structured behavioral modification (9.3% ± 0.4% vs. 5.1% ± 0.6% at 56 weeks). These findings support the use of intensive behavioral therapy alongside targeted pharmacologic antidepressants such as bupropion and naltrexone–bupropion to produce clinically meaningful weight loss in selected settings; however, findings for fluoxetine appear context-dependent. Because trials varied in populations, follow-up duration, and risk-of-bias domains, these findings should not be interpreted as prescriptive treatment recommendations.